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Research at Mass General
Read the Hochedlinger Lab 2017-2018 Annual Report
Konrad Hochedlinger, PhDProfessor of Medicine and Regenerative MedicineDepartment of Molecular Biology, Center for Regenerative Medicine, MGH Cancer Center, Harvard Medical School
The Hochedlinger laboratory explores the molecular mechanisms underlying pluripotency, which is the ability to produce all mature cell types of the body. Previous groundbreaking discoveries have shown that adult cells can be reprogrammed into pluripotent stem cells by activating a handful of embryonic genes. The resultant cells, called induced pluripotent stem cells (iPSCs), have tremendous therapeutic potential; they can be derived from any patient’s skin or blood cells. In the laboratory, iPSCs can be coaxed into many specialized cell types. Our lab has contributed to a better understanding of the process of cellular reprogramming, which allowed us to elucidate basic mechanisms that maintain cellular identity and prevent aberrant cell fate change. Our ultimate goal is to utilize these mechanistic insights for the development of new strategies to treat cancer and other complex diseases.
Konrad Hochedlinger, PhDPrincipal Investigator
The Hochedlinger lab is studying the mechanisms of cellular reprogramming using transcription-factor-mediated conversion of somatic cells into induced pluripotent stem (iPSCs). iPSCs are typically derived by retroviral transduction of the embryonic transcription factors Oct4, Sox2, c-Myc and Klf4, which reset the differentiation state of an adult cell into that of a pluripotent cell. The underlying transcriptional and epigenetic changes remain largely elusive due to the low efficiency of reprogramming and the heterogeneity of cell cultures. Importantly, iPSCs have been derived from different species—including human patients—and therefore provide a unique platform to model degenerative disorders such as Alzheimer’s disease, Parkinson’s disease and diabetes. Moreover, iPSCs could be ultimately used in regenerative medicine to replace damaged cells and tissues with genetically matched cells.
We have identiﬁed biomarkers to track and prospectively isolate rare intermediate cell populations that are poised to become iPSCs, and we are currently using these populations to understand the transcriptional, epigenetic and proteomic changes in cells undergoing reprogramming. In addition, we have shown that terminally differentiated beta cells and lymphocytes can be reprogrammed into iPSCs, thus demonstrating that induced pluripotency is not limited to rare adult stem cells as has originally been suggested. Nevertheless, we discovered that immature hematopoietic cells give rise to iPSCs more efficiently than any tested mature cell types, suggesting that the differentiation stage and therefore the epigenetic state of the starting cell has a profound effect on its potential to be reprogrammed. At the molecular level, we have identiﬁed the p53 and p16/p19 tumor suppressor pathways as well as the Tgf-beta signaling cascade as roadblocks during the reprogramming process, pointing out striking similarities between pluripotent cells and cancer cells. Additionally, our lab has conducted unbiased shRNA screens for barriers to reprogramming, uncovering new mechanisms that safeguard somatic cell identity. For example, we identified the histone chaperone CAF-1 and the protein modifier Sumo2 as novel modulators of mammalian cell fate change and we are currently exploring the underlying mechanisms as well as their role in tissue homeostasis and cancer.
One major roadblock for the therapeutic use of iPSCs has been the fact that integrating viruses were initially used to deliver the reprogramming genes to cells, resulting in genetically altered iPSCs. By using adenoviruses expressing the reprogramming factors transiently in cells, we were able to produce the first iPSCs devoid of any viral elements and thus any genetic manipulation. In addition to eliminating a potential roadblock to the therapeutic application of iPSC technology, this finding allowed us to compare unaltered iPSCs to genetically matched embryonic stem cells, which represent the gold standard for pluripotent stem cells. For example, we discovered that the Dlk1- Dio3 imprinted gene cluster is aberrantly silenced by hypermethylation in many iPSC lines, which correlates with their impaired developmental potential. We recently extended this study to human cells, demonstrating that isogenic, vector-free iPSCs are equivalent to human embryonic stem cells. These results indicated that genetic background and reprogramming method are major contributors of transcriptional and epigenetic variation in human pluripotent stem cell lines.
In a separate line of investigation, we are studying the role of Sox2 in adult tissues. While Sox2 has been mostly interrogated in the context of pluripotent stem cells and cellular reprogramming, recent data suggest that it may play important functions in adult tissues as well. For example, Sox2 is essential for neural stem cell maintenance, and its coding region is ampliﬁed in lung and esophageal cancer, thus implicating Sox2 in adult tissue regeneration and tumorigenesis. We have identiﬁed Sox2-expressing cells in several adult tissues where it has not previously been characterized, including squamous epithelia lining the stomach, anus and cervix as well as in testes, lens and glandular stomach. Unexpectedly, we discovered that Sox2 functions as a tumor suppressor in a mouse model of stomach cancer, which may have important therapeutic implications given its role as an oncogene in other tissues. Future work in the lab is aimed at further understanding the molecular and functional role of Sox2 and Sox2+ cells in stomach homeostasis and using mouse and human cells.
View a list of publications by researchers at the Hochedlinger Laboratory
Di Stefano B, Ueda M, Sabri S, Brumbaugh J, Huebner AJ, Sahakyan A, Clement K, Clowers KJ, Erickson AR, Shioda K, Gygi SP, Gu H, Shioda T, Meissner A, Takashima Y, Plath K, Hochedlinger K. Reduced MEK inhibition preserves genomic stability in naive human embryonic stem cells. Nat Methods. 2018 Aug 20. doi: 10.1038/s41592-018-0104-1. [Epub ahead of print]
Schwarz BA, Cetinbas M, Clement K, Walsh RM, Cheloufi S, Gu H, Langkabel J, Kamiya A, Schorle H, Meissner A, Sadreyev RI, Hochedlinger K. Prospective Isolation of Poised iPSC Intermediates Reveals Principles of Cellular Reprogramming. Cell Stem Cell. 2018 Jul 4. pii: S1934-5909(18)30295-9.
Brumbaugh J, Di Stefano B, Wang X, Borkent M1, Forouzmand E, Clowers KJ, Ji F4, Schwarz BA, Kalocsay M, Elledge SJ, Chen Y, Sadreyev RI, Gygi SP, Hu G, Shi Y, Hochedlinger K. Nudt21 Controls Cell Fate by Connecting Alternative Polyadenylation to Chromatin Signaling. Cell. 2018 Jan 11;172(1-2):106-120.e21. doi: 10.1016/j.cell.2017.11.023. Epub 2017 Dec 14.
Bar-Nur O, Gerli MFM, Di Stefano B, Almada AE, Galvin A, Coffey A, Huebner AJ, Feige P, Verheul C, Cheung P, Payzin-Dogru D, Paisant S, Anselmo A, Sadreyev RI, Ott HC, Tajbakhsh S, Rudnicki MA, Wagers AJ, Hochedlinger K. Direct Reprogramming of Mouse Fibroblasts into Functional Skeletal Muscle Progenitors. Stem Cell Reports. 2018 May 8;10(5):1505-1521.
Choi J, Huebner AJ, Clement C, Walsh RM, Savol A, Lin K, Gu H, Di Stefano B, Brumbaugh J, Kim SY, Sharif J, Rose CM, Mohammad A, Odajima J, Charron J, Shioda T, Gnirke A, Gygi SP, Koseki H, Sadreyev R, Xiao A, Meissner A & Hochedlinger K. Prolonged Mek1/2 suppression impairs the developmental potential of embryonic stem cells. Nature. 2017 Aug 10;548(7666):219-223.
Choi J, Clement K, Huebner AJ, Webster J, Rose CM, Brumbaugh J, Walsh RM, Lee S, Savol A, Etchegaray JP, Gu H, Boyle P, Elling , Mostoslavsky R, Sadreyev R, Park PJ, Gygi SP, Meissner A. & Hochedlinger K. DUSP9 Modulates DNA Hypomethylation in Female Mouse Pluripotent Stem Cells. Cell Stem Cell 20, 706-719 (2017).
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